| Objectives: Citalopram Hydrobromide is a highly selective 5-HT reuptake inhibitor (SSRI) which is widely used in a variety of depression treatment in clinics. The mechanism is by inhibiting 5-HT re-absorption and increase the 5- HT concentration of brain extracellular, and thus resistance to depression. It has the properties of fast onset of action, strong effect, few side effects and so on. But the long-term administration can easily lead to poor compliance, while oral administration would lead to large fluctuation in drug plasma concentration and easy to cause adverse reaction.Percutaneous absorption preparation is administered in the skin surface, then the drug penetrate the skin layers into the body circulation at a constant speed (or near constant speed) to make local or general treatment effect. Compared with the traditional drug delivery system, percutaneous absorption preparation can produce a lasting, constant and controllable blood concentration, thereby reducing adverse reactions,avoiding the liver first-pass effect. Patients can self-medication, remove the drug timely when problem occurs. Gel is a kind of percutaneous absorption preparation with the property of simple preparation process and easy to use. Based on the above considerations, the citalopram gel was formulated to improve the patients' compliance, avoid the peak-trough phenomenon of blood concentration and reduce adverse reactions.Methods: The basic physical and chemical properties of the drugs determine the speed of transdermal. UV method was developed to measure the physical and chemical properties of citalopram. The solubility of Citalopram in water and saline was measured, as well as the oil-water partition coefficient in water, saline, pH2.0, pH4.0, pH5.0, pH6.8, pH7.4, pH8.0 buffer solution in order to lay the foundation for the preparation of gel.The transdermal permeability across mouse skin of citalopram was studied by Franz diffusion cell with saline as receiving fluid. First, the effects of different pH value on the penetration were studied. Because the amount most of drugs through the skin was small which was difficult to meet the need of treatment,the effects of different penetration enhancers on penetration were studied, inclueding propylene glycol, 5% NMP, 5% menthol, 5% IPM, 10% oleic acid and 1%, 3%, 5%, 10% Azone. Percutaneous penetration kinetics curves were establishment to evaluate the enhancement of different penetration enhancers with penetrate speed and ER as indicators.On the basis of the studies mentioned above and the literature reported,the gel was explored. Selecting the cumulative amount of 12h in vitro percutaneous penetration as a indictor,the orthogonal experiment was designed to optimize formula in which the amount of matrix, drugs, penetration agents and penetration enhancers were taken as four influential factors. Then we evaluated optimal formulation of citalopram gels by content, transdermal permeation,permeation in vitro,prelimitary stability, skin irritation Pharmacokinetics study: SD rats were selected as experiment animal.One group was given solutions of citalopram, the other group was given gel. Plasma samples were obtained at different times and then analyzed by HPLC with Fluorescence detector. The various pharmacokinetic parameters were calculated by 3P97.Results: The solubility of Citalopram in water and saline were 44.71mg/ml and 52.96mg/ml respectively, indicating good water-soluble. With the gradual increase in pH, the oil-water partition coefficients of the drug gradually increased.While pH value increased to 7.4,the oil-water partition coefficients had few changes.Percutaneous penetration experiments showed that the percutaneous penetration of drug follower zero-rate. The cumulative amount of permeation per unit area time showed a good linear relationship with time. The pH had significant influence on percutaneous penetration .It was shown that with the augment of pH,the penetration rate increased too. In order to have a high penetration rate and good tolerance, pH7.4 was choosen for the follow-up study. The effects of enhancers were as followed: 5% NMP <5% Menthol <1% Azone |
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